A clear understanding of the pathology of any human disease is prerequisite for the identification of appropriate animal models and other approaches to develop methods of prevention and treatment. Two mechanisms have received the most support concerning diabetic neuropathy (DN), one of the commonest of neurological disorders. One indicates that nerve ischemia due to microangiopathy causes the neuropathy. The support for this in many cases includes the finding of focal fascicular lesions (FFL) similar to those found in vasculitic neuropathy in densities proportional to the distal loss of myelinate nerve fibers (MNF). However, for many cases distal loss of MNF is not accompanied by FFL and recent studies in our laboratory reveal axonal degenerative changes in the nucleus gracilus indicating that the condition is a central peripheral distal axonopathy (distal axonopathy). We propose to expand our collection of diabetic and nondiabetic subjects at autopsy and to sample from future cases additional sites in the peripheral nerve system as well as the gracilus tract and nucleus. To better define the role of ischemia we will perform morphometric studies of MNF densities and FFL at various locations in the PNS and search for quantitative abnormalities in the vasa nervorum. These studies will include 3D reconstruction of the vascular anatomy relating to localized sites of nerve ischemia. Our second goal is to quantitatively assess for evidence of axonal degenerative changes in the gracile tract and nucleus which will provide a measure for distal axonopathy. Statistical analysis will then be performed to identify the relative contributions of the underlying pathogenic mechanisms.